This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Influenza Pathogenesis &Immunology Research Center (IPIRC) is one of six national Influenza Centers of Excellence funded by NIH/NIAID. The objectives of this Center have been to determine the molecular, ecologic and/or environmental factors that influence the evolution, emergence, transmission and pathogenicity of influenza viruses, including studies on animal influenza viruses with pandemic potential;and to characterize the immune response to influenza vaccination to improve understanding of the immune correlates of protection and cross-protection. Most immune responses follow Burnet's rule in that antigen recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of "original antigenic sin" stands out as a paradox to Burnet's rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce antibodies against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the "original antigen" rather than to novel epitopes were described fifty years ago. We visited this issue to determine the extent to which original antigenic sin is induced by variant influenza viruses. Using two related strains of influenza A virus, we show that original antigenic sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we have been able to show that sequential infection of mice with two live influenza virus strains leads to almost exclusive antibody responses to the first viral strain, suggesting that original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system.